Project Summary The existence of a neuronal control of bone mass has received over the years many confirmations of various kind. Although those are by no means the only example of neuronal control of bone mass, the sympathetic nervous system inhibits bone mass accrual by hampering bone formation whereas the parasympathetic nervous system favors bone mass accrual. However, neuronal of regulation of bone mass accrual has never been explored as a possible means to explore bone mass phenotype caused by the absence of various osteoblast- derived proteins. Likewise, more often than not the importance of neuronal control of bone mass has not been studied in the craniofacial region. This is surprising since many osteoblasts in bones of the skull and face originate from neural crest cells. Osteocalcin is the most abundant non-collagenous protein of the bone extracellular matrix, the absence of which results in a poorly understood high bone mass phenotype. Osteocalcin is also an hormone and in that capacity it favors, following its binding to as novel receptor described in this application, the synthesis of catecholamine in the brain and thereby the activity of the sympathetic nervous system centrally. Independently of this function, as shown in another set of preliminary result of this application, osteocalcin signals through its first receptor described, Cyprc6a, to inhibit the activity of the parasympathetic nervous system. Both types of regulation of the autonomic nervous system by osteocalcin could hamper bone mass accrual. Hence, these preliminary data provide two possible mechanisms to explain what has never been explained until now: the high bone mass phenotype seen in mice lacking osteocalcin. We intend to address this question by studying the regulation of bone mass by osteocalcin in the craniofacial region, as well as in the rest of the skeleton. The Specific Aims of this application are: ? To determine whether an inactivation of Gpr158 in the forebrain will result in a high bone mass by decreasing the sympathetic tone. ? To determine whether an inactivation of Gprc6a in post-ganglionic parasympathetic neurons will result in a high bone mass phenotype. ? To test through rescue and genetic epistasis experiments whether osteocalcin regulation of the sympathetic and/or parasympathetic tone explains its regulation of bone mass accrual.